Abstract Previous research has shown that the stress-responsive regulation of protective Nrf2 target gene expression becomes progressively inefficient in aging Drosophila. This loss of responsiveness correlates with decreased fitness and an irreversible erosion of chromatin organization at Nrf2-regulated transcription units. We have developed genetic and pharmacological strategies that can delay the age-associated loss of signal- responsive Nrf2 target gene expression and chromatin disorganization. These effects can be achieved by MafS or Sirt6 overexpression, or by pharmacological treatments that stimulate Nrf2 function throughout adult life. When the Nrf2-mediated transcriptional stress response is thus preserved, older organisms show health benefits that are indicative of a slower rate of aging. These data suggest that the progressive loss of dynamic transcriptional responses to extracellular signals is caused by epigenetic decline and represents a major driver of aging. The discovery of strategies to delay this degenerative process can potentially guide the development of anti-aging interventions. The experimental program described in this proposal will advance the understanding of epigenetic aging at the mechanistic, molecular and genomic level. It will also test and optimize anti-aging strategies that target epigenetic mechanisms.